Abstract B061: Updated analysis of “CANCAP03” – A study into the pharmacodynamic biomarker effects of olaparib (PARP inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy
Authors: Harveer Dev, Mark Linch, Howard Kynaston, Greg Shaw, Krishna Narahari, Tatiana Hernández, Anne Warren, Alopa Malaviya, Vincent Gnanapragasam, Elizabeth Harrington, Niedzica Camacho, Silvia Glont, Massimo Sqautrito, Joshua Armenia, Luiza Moore, Robert Hanson, Toby Milne-Clarke, Shubha Anand, Charlie Massie, Nimish Shah, Simon Pacey
Journal: Cancer Research (2023)

Abstract Background: PARP inhibition with androgen deprivation is an effective treatment for Prostate Cancer (PC). We investigated the effects of a two-week course of olaparib±degarelix in the “window” before radical prostatectomy (RP). Methods: Primary endpoint: level of PARP inhibition. Secondary endpoints: safety and feasibility of the trial design. Exploratory endpoints: changes in relevant biological pathways after olaparib±degarelix. Participants (Pt) with localised PC (D’Amico intermediate or high risk) were randomly allocated (1:1) to receive olaparib 300mg bid for two weeks ± degarelix (240mg s/c). Recruitment target was twenty evaluable Pts. Compliance (patient diaries) and toxicity (CTCAE v4.03) were assessed. Diagnostic biopsies with subsequent prostatectomy samples were analysed by IHC for PAR protein expression and whole transcriptome gene expression analysis was performed using NovaSeq. Gene mutation profiling was performed using a custom 350 gene panel, sequenced on Illumina NextSeq 2000 and analysed with in-house bioinformatics pipeline. Serum samples for PSA and testosterone were taken at baseline, day 15 and 42 post RP. Results: 24 patients were recruited, 23 evaluable for safety and 20 for primary endpoint (11 olaparib, 9 olaparib+degarelix). All related AE ≤ Grade (Gr) 2, majority Gr 1. Commonest AEs: fatigue, nausea &amp; vomiting (olaparib) or injection site reaction, fatigue &amp; nausea (olaparib+degarelix). No RP was delayed by an AE. PSA declined from baseline in all (8/8) Pt after olaparib+degarelix and 3/9 Pt after olaparib (-11, -17 &amp; -47%). PAR protein expression decreased in both cohorts after treatment, with the mean reduction in PAR expression olaparib &amp;gt; olaparib+degarelix (p=0.01). After olaparib, Pt with greatest PSA change also had greatest reduction in PAR expression compared with other Pt (p=0.008); no correlation between PSA and PAR change was detected in olaparib+degarelix Pt. Pathogenic mutations (in BRCA2/ATM and ATM) were detected in two Pt. Upregulation of gene signatures, including homologous recombination signature, were noted following combined olaparib+degarelix treatment. Conclusions: We have previously reported that toxicities were predictable and manageable, with no drug-related delay in RP for Pt. Updated results confirm PARP inhibition (reduced PAR expression) in PC samples after olaparib and (to a lesser degree) olaparib+degarelix. Up-regulation of homologous recombination deficiency gene signature occurred after olaparib+degarelix. Further assessments of post-treatment tissues are ongoing to establish mechanisms of action of combination therapy across all genetic backgrounds. Citation Format: Harveer Dev, Mark Linch, Howard Kynaston, Greg Shaw, Krishna Narahari, Tatiana Hernández, Anne Warren, Alopa Malaviya, Vincent Gnanapragasam, Elizabeth Harrington, Niedzica Camacho, Silvia Glont, Massimo Sqautrito, Joshua Armenia, Luiza Moore, Robert Hanson, Toby Milne-Clarke, Shubha Anand, Charlie Massie, Nimish Shah, Simon Pacey. Updated analysis of “CANCAP03” – A study into the pharmacodynamic biomarker effects of olaparib (PARP inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B061.